CHAPTER 29 LECTURE NOTES

The vertebrate body possesses two mechanisms which protect it from potentially dangerous viruses, bacteria, other pathogens, and abnormal cells which could develop into cancer.

• One of these mechanisms is nonspecific, that is, it does not distinguish between infective agents.
• The second mechanism is specific in that it responds in a very specific manner (production of antibodies) to the particular type of infective agent.

I. Nonspecific mechanisms provide general barriers to infection

Nonspecific defense mechanisms help prevent entry and spread of invading microbes in an animal's body.

· An invading microbe must cross the external barrier formed by the skin and mucous membranes.

· If the external barrier is penetrated, the microbe encounters a second line of defense: interacting mechanisms of phagocytic white blood cells, antimicrobial proteins, and the inflammatory response.

1. The Skin and Mucous Membranes

The skin and mucous membranes act as physical barriers preventing entry of pathogens, and as chemical barriers of anti-pathogen secretions.

• In humans, oil and sweat gland secretions acidify the skin (pH 3 -5) which discourages microbial growth.
• The normal bacterial flora of the skin (adapted to the acidity) may release acids and other metabolic wastes to further inhibit pathogen growth.
• Saliva, tears and mucous secretions also wash away potential invading microbes in addition to containing antimicrobial proteins.
• An enzyme (lysozyme) in perspiration, tears, and saliva attacks the cell walls of many bacteria and destroys other microbes entering the respiratory system and eyes.
• In .the respiratory tract, nostril hairs filter inhaled particles and mucus traps microorganisms that are then swept out of the upper respiratory tract by cilia, thus preventing their entrance into the lungs.
• In the digestive tract, stomach acid kills many bacteria that enter with foods or those trapped in swallowed mucus from the upper respiratory system.

2. Phagocytic White Cells and Natural Killer Cells

Microbes that penetrate the skin or mucous membranes encounter amoeboid white blood cells capable of phagocytosis or cell lysis.

Neutrophils are cells that become phagocytic in infected tissue.

• Comprise 60% -70% of total white cells-
• Attracted by chemical signals, they enter infected tissues by amoeboid movement; only live a few days as they destroy themselves when destroying pathogens.

Monocytes comprise only about 5% of the total white blood cells. They mature, circulate for a few hours, then migrate to the tissues where they enlarge and become macrophages.

Macrophages are large amoeboid cells that use pseudopodia to phagocytize microbes that are destroyed by digestive enzymes and reactive forms of oxygen within the cell.

• Most wander through interstitial fluid phagocytosing bacteria, viruses and cell debris-
• Some reside permanently in organs and connective tissues. They are fIXed in place,but are located where they will have contact with infectious agents circulating in the blood and lymph.
• Fixed macrophages are especially numerous in the lymph nodes and spleen.

Eosinophils represent about 1.5% of the total white cell count but have limited phagocytic activity.

• Contain destructive enzymes in cytoplasmic granules which are discharged against the outer covering of the invading pathogen.
• Main contributioRisdefense against larger invaders such as parasitic worms.

Natural killer cells destroy the body's own infected cells, especially those harboring viruses.

• Also assault aberrant cells that could form tumors.
• Are not phagocytic, but attack the membrane, causing cell lysis.

C. Antimicrobial Proteins

A number of proteins function in nonspecific defense by either directly attacking

microorganisms or impeding their reproduction.

The two most important nonspecific protein groups are complement proteins and the

interferans.

The complement system is a group of at least 20 proteins which interact with other defense mechanisms.

• These proteins interact in a series of steps which results in lysis of the invading microbes.
• Some components of the system function in chemotaxis as attractants to stimulate phagocyte movement into the infected site.

The interferons are substances produced by virus-infected cells which help other cells resist infection by the virus-

• First discovered in 1957, three major types have been identified: alpha, beta, and gamma.
• They are secreted by infected cells as a nonspecific defense earlier than specific antibodies appear .
• Cannot save the infected cell, but their diffusion to neighboring cells stimulates production of proteins in those cells that inhibit viral replication.
• Not a virus-specific defense; interferon produced to infection by one strain of virus produces resistance in cells to other unrelated viruses-
• Most effective against short-term infections (colds and influenza).
• Interferon-garnma also activates phagocytes which enhances their ability to ingest and kill microorganisms.
• Interferons are now being mass produced using recombinant DNA technology and are being tested as treatments for viral infections and cancer.

D. The Inflammatory Response

A localized inflammatory response occurs when there is damage to a tissue due to physical injury or entry of microorganisms.

• Vasodilation of small vessels near the injury increases the blood supply to the area which produces the characteristic redness.
• The dilated vessels become more permeable allowing fluids to move into suuounding tissues resulting in localized edema. (Chemical signals are important in initiating an inflammatory response. (See Campbell, Figure 39.5)
• Histamine is released from injured circulating basophils and mast cells in the connective tissue.

=> Released histamine causes localized vasodilation and the capillaries in the area become leakier.

• Prostaglandins are also released from white blood cells and damaged tissues-

=> These and other substances promote increased blood flow to the injured area-

• Increased blood flow to the site of injury delivers clotting elements which help block the spread of pathogenic microbes and begin the repair process.

Migration of phagocytic cells into the injured area is also a result of increased blood flow

and increased leakage from the capillaries.

• Phagocytes are attracted to the damaged tissues by several chemical mediators including some complement system proteins.
• Neutrophils auive fIrst, followed closely by monocytes which develop into macrophages.
• The neutrophils eliminate microorganisms and then die.
• Macrophages destroy pathogens and clean up the remains of damaged tissue cells and dead neutrophils.
• Dead cells and fluid leaked from the capillaries may accumulate as pus in the area before it is absorbed by the body.

More widespread (systemic) inflammatory responses may also occur in cases of severe

infections (meningitis, appendicitis).

• The bone mauow may be stimulated to release more neutrophils by molecules emitted by injured cells-
• There may also be a severaIfold increase in the number of leukocytes within a few hours of response onset.
• A fever may develop in response to toxins produced by pathogens or due to pyrogens released by leukocytes.
• While a high fever is dangerous, moderate fevers inhibit the growth of some microorganisms.
• Moderate fevers may facilitate phagocytosis and speed up tissue repairs.

II. The immune system defends the body against specific invaders: an overview

A. Key Features of the Immune System

The immune system is the body's third line of defense and is very specific in its response.

• Distinguished from nonspecific defenses by: specificity, diversity, self/nopself recognition, and memory.

Specificity refers to this system's ability to recognize and eliminate particular

microorganisms and foreign molecules.

Antigen = A foreign substance that elicits an immune response.

Antibody = An antigen-binding immunoglobulin (protein), produced by B cells, that functions as the effector in an immune response.

• Antigens may be molecules exhibited on the surface of, produced by, or released from bacteria, viruses, fungi, protozoans, parasitic worms, pollen, insect venom, transplanted organs, or wom-out cells.
• Each antigen has a unique molecular shape and stimulates production of an antibody that defends specifically against that particular antigen-
• The immune response is thus very specific and distinguishes between even closely related invaders.

Diversity refers to the immune system's ability to respond to numerous kinds of invaders which are recognized by their antigenic markers.

• Based on the wide variety of lymphocyte populations in the immune system.
• Each population of antibody-producing lymphocytes is stimulated by a specific antigen; the stimulated lymphocytes synthesize and secrete the appropriate antibody.

Memory refers to the immune system's ability to recognize previously encountered antigens and to react faster and more effectively to subsequent exposures.

• This acquired immunity has long been recognized as a resistance to some infections encountered earlier in life (e.g. chicken pox).

Self/nonself recognition is the ability of the immune system to distinguish between the body's own molecules and foreign molecules (antigens).

• Failure of this system leads to autoimmune disorders which destroy the body's own tissues.

B. Active Versus Passive Acquired Immunity

Active immunity is the immunity conferred by recovery from an infectious disease-

• Depends on response by the person's own immune system.
• May be acquired naturally from an infection to the body or artificialIy by vaccination.
• Vaccines may be inactivated bacterial toxins, killed microorganisms, or weakened living microorganisms.

=> In all cases the organisms can no longer cause the disease but can act as antigens and stimulate an immune response.

• A person vaccinated against an infectious agent will show the same rapid, memory-based immunological response upon encountering the pathogen as someone who has had the disease.

Passive immunity is immunity which has been transferred from one individual to another by the transfer of antibodies.

• Natural occurrence when antibodies cross the placenta from a pregnant woman's system to her fetus-
• Passive immunity provides temporary protection to newborns whose immune systems are not fully operational at birth.
• Some antibodies are transferred to nursing infants though the milk.
• Persists for only a few weeks or months after which the infant's own system defends its body.
• May also be transferred artificially from an animal or human already immune to them disease.

=> Rabies is treated by injecting antibodies from people vaccinated against rabies; produces an immediate immunity important to quickly progressing infections.

=> Artificial passive immunity is of short duration but permits the body's own immune system to begin to produce antibodies against the rabies virus.

3. Humoral Immunity and Cell-Mediated Immunity

The body will mount either a humoral response or a cell-mediated response depending on

the antigen which stimulates the system.

Humoral immunity produces antibodies in response to toxins, free bacteria, and viruses

present in the body fluids.

• Antibodies to these types of antigens are synthesized by certain lymphocytes and then secreted as soluble proteins which circulate through the body in blood plasma and lymph.

Cell-mediated immunity is the response to intracellular bacteria and viruses, fungi,

protozoans, worms, transplanted tissues, and cancer cells.

• Depends on the direct action of certain types of lymphocytes rather than antibodies.

4. Cells of the Immune System

Lymphocytes are responsible for both humoral and cell-mediate immunity; the different

responses are due to the two main classes of lymphocytes in the body: B cells and T cells .

• Early B and T cells (as well as other lymphocytes) develop from multipotent stem cells in the bone marrow and are very much alike, they only differentiate after reaching their site of maturation.
• B cells (B lymphocytes) are responsible for the humoral immune response.

=> They form in the bone marrow and remain there to complete their maturation.

• T cells (T lymphocytes) are responsible for the cell-mediated immune response.

=> They also form in the bone marrow, then migrate to the thymus gland to mature.

Mature B cells and T cells are concentrated in the lymph nodes, spleen, and other lymphatic organs.

• These positions place lymphocytes where they are most likely to contact antigens-
• Antigen receptors are present on the membranes of both B cells and T cells.
• The antigen receptors on a B cell are membrane-bound antibody molecules which will recognize specific antigens.
• The T cell antigen receptors are proteins (not antibodies) embedded in the membrane which recognize specific antigens.

Effector cells are the cells which actually defend the body during an immune response.

• Effector cells are populations of cells resulting from division of lymphocytes which were activated by the binding of antigens to their antigen receptors.
• Activated B cells give rise to effector cells called plasma cells which secrete antibodies (humoral response) that eliminate the activating antigen-
• Activated T cells may produce two types of effector cells: cytotoxic T cells which destroy infected cells and cancer cells; and helper T cells which secrete cytokines.

Cyokine = Molecules secreted by one cell as a regulator of neighboring cells.

• Cytokines help regulate both B and T cells and thus are involved in both the humoral and cell-mediated responses.

II. Clonal selection of lymphocytes is the cellular basis for immunological specificity and diversity

The ability of the immune system to respond to the wide variety of antigens which enter the body is based in the enormous diversity of antigen-specific lymphocytes present in the system.

· Each lymphocyte will recognize and respond to only one antigen.

· This specificity is determined during embryonic development before any antigens are encountered, and is the consequence of the antigen receptor on the lymphocyte's surface.

· When an antigen enters the body and binds to receptors on the specific lymphocytes, those lymphocytes are activated and begin to divide.

=> The divisions produce a large number of identical effector cells (clones) which bind to the antigen that stimulated the response.

=> If, for example, a B cell is activated, it will proliferate to produce a large number of plasma cells that will each secrete an antibody which functions as an antigen receptor for the specific antigen that activated the original B cell.

• Each antigen thus activates only a small number of the diverse group of lymphocytes. The activated cells proliferate to produce a clone of millions of effector cells which are specific for the original antigen (clonal selection).

Clonal selection = Antigenic-specific selection of a lymphocyte that activates it to produce clones of effector cells dedicated to eliminating the antigen that provoked the initial immune response.

IV .Memory cells function in secondary immune responses

The primary immune response is the proliferation of lymphocytes to form clones of effector cells specific to an antigen during the body's first exposure to the antigen.

• There is a 5 to 10 day lag period between exposure and maximum production of effector cells.
• The lymphocytes selected by the antigen are differentiating into effector T cells and plasma cells during the lag period.

A secondary immune response occurs when the body is exposed to a previously encountered antigen.

• The response is faster (3 to 5 days) and more prolonged than a primary response.
• The antibodies produced are also more effective at binding the antigen.

This ability to recognize a previously encountered antigen is known as immunological memory.

• Based on memory cells which are produced during clonal selection for effectors in a primary immune response.
• Memory cells are not active during the primary response and survive in the system for long periods. (Effector cells produced in the primary response are active and, thus, short-lived.)
• When the same antigen that caused a primary immune response again enters the body, the memory cells are activated and rapidly proliferate to form a new clone of effector cells and memory cells-
• These new clones of effector and memory cells are the secondary immune response.

V. Molecular markers on cell surfaces function in self/nonself recognition

Antigen receptors on the surfaces of lymphocytes are responsible for detecting foreign molecules that enter the body. There are no lymphocytes reactive against the body's own molecules under normal conditions.

Self -tolerance = The lack of a destructive immune response to the body's own cells.

• Develops before birth when T and B lymphocytes begin to mature in the thymus and bone marrow of the embryo.
• Any lymphocytes with receptors for molecules present in the body at that time are destroyed; consequently, the body contains no lymphocytes with antigen receptors for its own molecules, only for foreign molecules.

The major histocompatibility complex (MHC or HIA in humans) is a group of glycoproteins embedded in the plasma membranes of cells.

• Important "self-markers" coded for by a family of genes.
• There are at least 20 MHC genes and at least 100 alleles for each gene.
• The probability that two individuals will have matching MHC sets is virtually zero unless they are identical twins.
• There are two main classes of MHC molecules in the body:

=> Class I MHC molecules are located on all nucleated cells of the body.

=> Class II MHC molecules are found only on specialized cells such as macrophages, B

cells, and activated T cells.

• Class II MHC molecules are important in interactions between cells of the immune system.

VI. In the humoral response, B cells defend against pathogens in body fluids by

generating specific antibodies

The humoral response occurs when an antigen binds to B cell receptors which are specific for the antigen epitopes.

• The B cells differentiate into a clone of plasma cells which begin to secrete antibodies.
• These antibodies are most effective against pathogens circulating in the blood or lymph.
• Memory cells are also produced and form the basis for secondary immune responses.

A. The Activation of B Cells

The selective activation of a B cell by an antigen results in the formation of a clone of

plasma cells and memory cells. This is often a two-step process.

• One step is the binding of the antigen to specific antigen-receptors on the surface of the B cell.

The other step in B cell activation involves macrophages and helper T cells; this step ends with the production of plasma cells. (See Campbell, Figure 39.9)

• Mter macrophages phagocytize pathogens, pieces of the partially digested antigen molecules are bound to class II MHC molecules which are moved to and presented on the surface of the macrophage.
• These presented antigen molecules in complexes with class n MHC proteins result in the macrophage functioning as an antigen-presenting cell.
• A helper T cell with a receptor specific for the presented antigen binds to the self/nonself class n MHC protein-antigen complex.
• The T cell is activated by contact with the macrophage and proliferates to form a clone of helper T cells specific for the presented antigen-
• These helper T cells secrete cytokines which stimulate B cells that have encountered the same antigen; recognition of these B cells also involves a class n MHC protein-antigen complex to which the receptor on the T cell binds.
• The T cell contact activates these B cells to form a clone of plasma cells.
• Each plasma cell (= effector cell) then secretes antibodies specific for the antigen.

Both macrophages and B cells act as antigen-presenting cells in their interactions with helper T cells, but there is one major difference:

• Each macrophage can display a number of different antigens depending on the type of pathogen phagocytized.
• B cells are specific and can bind to and display only one type of antigen-
• Macrophages, which are nonspecific, can thus enhance specific defense by selectively activating helper T cells which in turn activate B cells specific for the antigen.
• Helper T cells are also antigen-specific and are activated only by macrophages presenting the proper class II MHC protein-antigen complex.

B. T -Dependent and T -Independent Antigens

Antigens may be either T -dependent or T -independent.

T -dependent antigens = Antigens that evoke the cooperative response involving

macrophages, helper T cells, and B cells.

• These antigens cannot stimulate antibody production without T cell involvement.
• Most antigens are T -dependent.
• Memory cells are produced in T -dependent responses.

T -independent antigens = Antigens that trigger humoral immune responses without macrophage or T cell involvement.

• Usually long chains of repeating units such as polysaccharides or protein subunits often found in bacterial capsules and flagella.
• B cells are stimulated directly by the antigen which probably binds simultaneously to several antigen receptors on the B cell surface.
• The antibody production (humoral response) is usually much weaker to that of T- dependent antigens.
• No memory cells are generated in T -independent responses.

Whether activated by T -dependent or T -independent antigens, a B cell gives rise to a clone of plasma cells

• Each of these effector cells secretes up to 2,000 antibodies per second into the body fluids for its 4 to 5 day lifespan.
• The specific antibodies help eliminate the foreign invader from the body.

C. The Molecular Basis of Antigen-Antibody Specificity

Antigens are usually proteins or large polysaccharides that make up a portion of the outer

covering of pathogens or transplanted cells.

• May be components of the coats of viruses, capsules and cell walls of bacteria, or surface molecules of other cell types-
• Molecules on the cell surface of transplanted tissues and organs or blood cells from other individuals are also recognized as foreign.
• Antibodies recognize a localized region on the surface of an antigen (the epitope), not the entire antigen molecule. (See Campbell, Figure 39.10)

Epitope = On an antigen' s surface, a localized region that is chemically recognized by

antibodies; also called an antigenic determinant.

• Several types of antibodies from several different B cells may be produced to a single bacterial cell since it may have different antigens on different areas and each bacterial antigen may possess more than one recognizable epitope.

Antibodies comprise a specific class of proteins called immunoglobulins (Igs). (See

Campbell, Figure 39.11a)

• The structure of the immunoglobulin is associated with its function.
• Antibodies are Y -shaped molecules comprised of four polypeptide chains: two identical light chains and two identical heavy chains-
• All four chains have constant (C) regions that vary little in amino acid sequence among antibodies that perform a particular type of defense.
• At the tips of the Y are found variable (V) regions in all four chains; the amino acid sequences in the variable region show extensive variation from antibody to antibody.
• The variable regions function as antigen-binding sites and their amino acid sequences result in specific shapes that fit and bind to specific antigen epitopes.
• The antigen-binding site is responsible for the antibody's ability to identify its specific antigen epitope and the stem (constant) regions are responsible for the mechanism by which the antibody inactivates or destroys the antigenic invader.

There are five types of constant regions, each of which characterizes one of the five major classes of mammalian immunoglobins. (See Table 39.1 for a summary .)

• IgM. Consists of five Y -shaped monomers arranged in a pentamer structure. Circulating antibodies which appear in response to an initial exposure to an antigen.
• IgG. A Y-shaped monomer. Most abundant circulating antibody; readily crosses blood vessels and enters tissue fluids; protects against bacteria, viruses, and toxins circulating in blood and lymph; triggers complement system action.

• IgA. A dimer consisting of two Y -shaped monomers. Produced primarily by cells abundant in mucous membranes; prevents attachment of bacteria and viruses to epithelial surfaces; also found in saliva, tears, perspiration, and colostrum.
• IgD. A Y-shaped monomer. Found primarily on external membranes of B cells; probably functions as an antigen-receptor which initiates differentiation of B cells.
• IgE. A Y -shaped monomer. Stem regions attach to receptors on mast cells and basophils; stimulates these cells to release histamine and other chemicals that cause allergic reactions when triggered by an antigen.

D. How Antibodies Work

Antibodies do not directly destroy an antigenic pathogen. The antibody binds to the antigen to form an antigen-antibody complex which tags the invader for destruction by one of several effector mechanisms. (See Campbell, Figure 39.12)

• Neutralization is the simplest mechanism.

=> The antibody blocks viral attachment sites or coats a bacterial toxin, making them

ineffective. Phagocytic cells eventually destroy the complex.

• Agglutination is another mechanism.

=> Each antibody has two or more antigen-binding sites and can cross-link adjacent antigens. The cross-linking can result in clumps of a bacteria being held together by the antibodies, making it easier for phagocytes to engulf the mass.

• Precipitation is similar to agglutination but involves the cross-linking of soluble antigen molecules instead of cells.

=> These immobile precipitates are easily engulfed by phagocytes.

• Activation of the complement system is another mechanism.

=> Antibodies combine with complement proteins; this combination activates the complement proteins which produce lesions in the foreign cell's membrane that result in cell lysis.

E. Monoclonal Antibody Technology

A new method of obtaining antibodies which did not depend on the polyclonal antibodies isolated from the blood of immunized animals was developed in 1975.

• This new method produced monoclonal antibodies .

Monoclonal antibodies = Defensive proteins produced by cells descended from a single cell; all antibodies produced by these cells are identical.

This technology permits the production of large quantities of antibodies quickly and at

relatively little expense. These monoclonal antibodies:

• Can be used in diagnostic labs to detect pathogenic microbes in clinical samples.
• Form the basis for over-the-counter pregnancy tests.
• Are used as therapeutic agents.
• Show promise in treating cancer when combined with a toxin that would destroy the cancer cell.

Monoclonal antibodies are produced by hybridoma cells.

• Hybridoma cells are hybrid cells resulting from the fusion of certain cancer cells (myelomas) with normal antibody-producing plasma cells.
• The cancer cell is used since it can be cultured indefmitely ( other cells can only be cultured for a few generations).
• Plasma cells expressing the desired antibody are mixed with myeloma cells and some of the two cell types fuse-
• The hybridoma cells are isolated and cultured.

=> These cells exhibit the key qualities of the two cell types.

=> They will produce a single type of antibody and can be cultured indefmitely to manufacture that antibody on a large scale.

VII. In the cell-mediated response, T cells defend against intracellular pathogens

The humoral immune response is that portion of the body's defenses that identifies and destroys extracellular pathogens.

The cell-mediated immune response is the defense mechanism that combats pathogens that have already entered cells.

• The key components of cell-rnediated immunity are helper T cells (T ~ and cytotoxic T cells (Tc).
• These lymphocytes complete their maturation in the thymus and migrate to lymphoid organs such as the spleen and lymph nodes.

A. The Activation of T Cells

T cells respond only to antigenic epitopes displayed on the surfaces of the body's own cells.

• T cells cannot detect free antigens in the body fluids-
• Specific T -cell receptors embedded in the T cell plasma membrane recognize the bound antigens.
• The receptor of a helper T cell (T ~ recognizes the molecular combination of an antigen fragment with a class II MHC.
• The receptor of a cytotoxic T cell (T c) recognizes the combination of an antigen fragment with a class I MHC molecule-
• The antigen is nestled within the MHC protein in both cases.
• While an MHC molecule can associate with a variety of antigens, each combination is a unique complex recognized by specific T cells.

The presence of a T cell surface molecule called CD4 enhances the interaction between T H cells and antigen-presenting cells (A PC).

• CD4 is present on most T H cells and has an affmity for a part of the class II MHC molecule.
• The CD4-class II MHC interaction helps keep the T H cell and APC engaged while antigen specific contact is occurring. (See Campbell, Figure 39.13)
• T c cells carry a surface molecule called CD8 which has an affmity for class I MHC molecules.

The MHC-antigen complex displayed on an infected body cell stimulates T cells with the

proper receptor to multiply and form clones of activated T H and T c cells which recognized the pathogen.

• T H cells stimulate B cells to secrete antibodies against T -dependent antigens in a humoral response.
• T H cells also activate other types of T cells to mount cell-rnediated responses to antigens.

Helper T cells (T H) are able to stimulate other lymphocytes by receiving and sending cytokines.

• When a T H cell binds to an antigen-presenting macrophage, the macrophage releases interleukin-l (a cytokine).
• The presence of interleukin-l stimulates the T H cell to release its own cytokine, interleukm-2.
• In a positive feedback mechanism, interleukin-2 stimulates TH cells to grow and divide more rapidly; this results in the production of more T H cells and an increased supply of interleukin- 2.
• The humoral response against the antigen is enhanced b~ause interleukin-2 and other cytokines secreted by the increasing numbers of T H cells activate B cells.
• The increased levels of cytokines also increase the cell-mediated response by stimulating another class of T lymphocytes to differentiate into cyto toxic T cells (effector cells).

B. How Cytotoxic T Cells Work

Cytotoxic T cells (T c) are the cells which actually destroy infected host cells-

• Host cells infected by viruses and other pathogens display antigens complexed with class I MHC molecules on their surfaces-
• T c cells have specific receptors which recognize and bind to antigen-class I MHC markers. (Note that this differs from T H cells which bind to antigen-class II MHC complexes.)
• The T c receptor can bind to any cell in the body displaying the antigen-class I MHC marker since class I MHC is present on all nucleated cells-
• When a T c cell binds to an infected cell, it releases perform which is a protein that forms a lesion in the infected cell's membrane.
• Cytoplasm escapes through the lesion and eventually cell lysis occurs.
• Destruction of the host cell not only removes the site where pathogens can reproduce, but also exposes the pathogens to circulating antibodies from the humoral response.
• T c cells continue to live after destroying the infected cell and may kill many others displaying the same antigen-class I MHC marker.

Cytotoxic T cells also function to destroy cancer cells which develop periodically in the

body.

• Cancer cells possess distinctive markers not found on normal cells-
• T c cells recognize these markers as nonself and attach and lyse the cancer cells-
• Cancers develop primarily in individuals with defective or declining immune systems.

A third type of T lymphocyte, suppressor T cells (T s), has been found in the body.

• Probably function to suppress the immune system when an antigen is no longer present.
• Action is not well understood and some immunologists feel T s cells are actually a form of Ts cells.

VII. Complement proteins participate in both nonspecific and specific defenses

The 20 or so complement proteins circulate in the blood in inactive forms.

• These proteins become activated in a series fashion with each activating the next in the series.

The classical pathway describes complement's activation in the specific defense mechanism. (See Campbell, Figure 39.16)

• Initiated when antibodies bind to a specific pathogen which targets the cell for destruction.
• A complement protein attaches to, and bridges the gap between, two adjacent antibody molecules.
• The antibody-complement association activates complement proteins to form, in a step-by- step sequence, a membrane attack complex.
• The membrane attack complex lyses the pathogen's membrane producing a lesion.
• Lysis of the pathogenic cell then occurs.

The alternative pathway is how complement is activated in nonspecific defense mechanisms.

• Does not require cooperation with antibodies.
• Complement proteins are activated by substances found in many pathogens (yeasts, viruses, virus-infected cells, protozoans) to form a membrane attack complex.
• The complex lyses the pathogen without the aid of antibodies.
• Complement proteins also contribute to inflammation by binding to histamine-containing cells; this association triggers the release of histamine from those cells-
• Several complement proteins also attract phagocytic cells to infected sites. Complement and phagocytes also work together in two ways to destroy pathogens.
• Opsonization is a cooperative mechanism in which complement proteins attach to a foreign cell and stimulate phagocytes to engulf the cell.
• In immune adherence, complement proteins and antibodies coat a microbe which causes it to adhere to blood vessel walls and other surfaces; this makes the cell easy prey for circulating phagocytes.

IX. The immune system's capacity to distinguish self from nonself is critical in blood

transfusion and transplantation

The body's immune system distinguishes between self (the body's own cells) and nonself (foreign cells).

• Nonself includes not only the pathogens discussed earlier, but also cells from other individuals of the same species.

A. Blood Groups

The human ABO blood groups provide a good example for nonself recognition. The antigenpresent on the surface of the erythrocytes is not antigenic to that person but may be recognized as foreign if placed in the body of another individual.

• Individuals of blood type A have the A antigen and make anti-B antibodies.
• Individuals of blood type B have the B antigen and make anti-A antibodies.
• Individuals of blood type AB have the A and B antigen and make no antibodies.
• Individuals of blood type O have neither the A nor B antigen and make anti-A and anti-B antibodies.

Blood group antibodies can cause blood of a different antigenic type to agglutinate, a life- threatening reaction.

• Type O individuals are universal donors since their blood has neither antigen.
• Type AB individuals are universal recipients since they produce neither antibody A or antibody B .
• The blood group antibodies are present in the body before a transfusion occurs as they form in response to the bodies normal bacterial flora and cross-react with blood group antigens.

=> Usually IgM class antibodies do not cross the placenta, thus they present no harm to a developing fetus with a blood type different from the mother.

The Rh factor is another blood group antigen. Rh factor causes problems when a mother is Rh negative and her fetus is Rh positive (inherited from the father).

• When small amounts of fetal blood cross the placenta and come into contact with the mother's lymphocytes, the mother develops antibodies against the Rh factor.
• Usually only a problem in the second child since the response will be quick due to sensitization and formation of memory cells during the first baby's gestation.

=> Unlike blood group antibodies, Rh antibodies are IgG class which can cross the placenta.

=> The mother's antibodies cross the placenta and destroy the red blood cells of then Rh positive fetus.

• Can be prevented by injection of anti-Rh antibodies which destroy Rh-positive red cells before the mother develops immunological memory .

B. Tissue Grafts and Organ Transplants

The MHC is a biochemical fmgerprint unique to each individual.

• Remember there are at least 20 MHC genes and about 50 alleles for each gene.
• Complicates tissue grafts and organ transplants since foreign MHC molecules are antigens and cause cytotoxic T cells to mount a cell-mediated response.
• Cyclosporine and FK506 suppress cell-mediated immunity without crippling humoral immunity, thus increasing the chance of successful grafts aitd transplants.

Note the reactions of the immune system to transfusions, tissue grafts, and organ transplants are normal reactions of a healthy immune system, not disorders of the system.

X. Abnormal immune function leads to disease states

A. Autoimmune Diseases

Autoimmune Disease = The immune system reacts against self.

• Some cases involve immune reactions against components of the body's own cells which are released by the normal breakdown of skin and other tissues; especially nucleic acids in lupus erythematous.
• Rheumatoid arthritis is an autoimmune disease in which inflammation damages cartilage and bones in joints.
• Destruction of insulin-producing pancreas cells by an autoimmune reaction appears to cause insulin-dependent diabetes.
• Antibodies produced to repeated streptococcal infections may react with heart tissues and cause valve damage in some people.
• Other autoimmune diseases are Grave's disease and rheumatic fever.

B. Allergy

Allergy = A hypersensitivity of the body's defense system to an environmental antigen called an allergen.

• Some believe these reactions to be evolutionary remnants to infection by parasitic worms due to similarities in the responses.

IgE class antibodies are commonly involved in allergic reactions; these antibodies recognize pollen as allergens. (See Campbell, Table 39.1)

• IgE antibodies attach by their tails to noncirculating mast cells found in connective tissues.
• When a pollen grain bridges the gap between two adjacent IgE monomers, the mast cell responds with a reaction called degranulation.
• Degranulation involves the release of histamine and other inflammatory agents.
• Histamine causes dilation and increased permeability of small blood vessels which results in the common symptoms of an allergy .
• Antihistamines are drugs used to treat allergies since they interfere with the action of histamine.

Anaphylactic shock is a life-threatening reaction to injected or ingested antigens; it is the most serious type of acute allergic response.

• Occurs when mast cell degranulation causes a sudden dilation of peripheral blood vessels and a drastic drop in blood pressure.
• Death may occur in a few minutes.
• This hypersensitivity may be associated with foods (peanuts, fish) or insect venoms (wasp or bee stings).
• Epinephrine may be injected to counteract the allergic response.

C. Immunodeficiency

Immunodeficiency refers to a condition where an individual is inherently deficient in either humoral or cell-mediated immune defenses.

• Severe combined immunodeficiency (SCID) is a congenital disorder in which both the humoral and cell-mediated immune defenses fail to function.
• Gene therapy has had some success in the treatment of a type of SCID where there is a deficiency of the enzyme adenosine deaminase.

Not all cases of immunodeficiency are inborn conditions.

• Some cancers, like Hodgkin's disease, damage the lymphatic system and make the individual susceptible to infection.
• Some viral infections cause depression of the immune system (i.e. AIDS).
• Physical and emotional stress may compromise the system; adrenal hormones secreted by stressed individuals affect the number of leukocytes and may suppress the system in other ways.

Evidence suggests direct links between the nervous system and the immune system.

• There is a network of nerve fibers which penetrates into lymphoid tissues including the thymus.
• Lymphocytes have also been found to possess surface receptors for chemical signals secreted by nerve cells.

D. Acquired Immunodeficiency Syndrome (AIDS)

Acquired immunodeficiency syndrome is a severe immune system disorder caused by infection with the human immunodeficiency virus (HlV).

• Characterized by a reduction of T cells and the appearance of characteristic secondary infections.
• Mortality rate approaches 100%. .
• HIV probably evolved from another virus in central Mrica and may have gone unrecognized for many years-
• HIV infects cells, including TH cells, which carry the CD4 receptor on their surface.
• A glycoprotein on the HIV envelope binds specifically to the CD4 receptor.

=> After attaching, the HIV enters the cell and begins to replicate-

=> Newly formed viruses bud continuously from the host cell, circulate, and infectm other cells.

• Infected cells may be killed quickly by the virus or by the immune response; they may also live for an extended time.
• The immune system is devastated by HIV since the virus targets T H cells which playa central role in both the humoral and cell-mediated responses.

=> Macrophages and a few subclasses of B cells carrying the CD4 receptor can also be infected.

• The HIV may also remain as a provirus in the infected cell genome for many years before becoming active.

HIV is not eliminated from the body by antibodies for several reasons:

• The latent provirus is invisible to the immune system.
• The virus undergoes rapid mutational changes in antigens during replication which eventually overwhelms the immune system.
• The population of helper T -cells eventually declines to the point where cell-mediated immunity collapses.
• Secondary infections characteristic of HIV infection develop (Pneumocystis pneumonia and Kaposi's sarcoma).

AIDS is the late stage of HIV infection and is defmed by a reduced T cell population and the appearance of secondary infections.

• Takes an average of about ten years to reach this stage of infection.
• During most of this time, only moderate symptoms are shown.
• Progression of infection is more rapid in irtfants who were infected in utero.
• Individuals exposed to HIV have circulating antibodies that can be detected; displaying these antibodies designates and individual as HIV-positive.

HIV is only transmitted through the transfer of body fluids, blood or semen, containing

infected cells.

• Most commonly transmitted in the U.S. and Europe through unprotected sex between male homosexuals and unsterilized needles in intravenous drug users.
• In Africa and Asia, transmission through unprotected heterosexual sex is rapidly increasing; especially in areas with a high incidence of other sexually transmitted diseases.
• Transmission to nursing infants through breast milk has been reported.
• Transmission through blood transfusions has also been reported, but the incidence has declined greatly with implementation of screening procedures.

.

AIDS is currently considered an incurable disease-

• AZT, ddC, and ddI are antiviral drugs used to extend the lives of infected individuals-

=> They do not eliminate the virus but inhibit the viral enzyme reverse transcriptase.

• Other drugs are used to fight opportunistic infections common in AIDS patients.
• The best way to prevent additional infections is to educate people on how the disease is transmitted and how to protect themselves.

XI. Invertebrates exhibit a rudimentary immune system

How invertebrates react against pathogens that enter their bodies is poorly understood, although it is known that they have a well developed ability to distinguish self from nonself.

• Experiments have shown that if the cells from two sponges of the same species are mixed, the cells from each individual will aggregate in separate groups, excluding cells from the other individual. "
• Coelomocytes, amoeboid cells that destroy foreign materials, have been found in many invertebrates.

A memory response has also been identified in earthworms.

• A body wall graft from one worm to another will survive for about eight months before rejection if the worms are from the same population.
• A graft involving worms from different populations is rejected in two weeks.
• A second graft from the same donor to the same recipient is rejected in less than one week due to coelomocyte activity.